1,2-Dihydroindene-2-spiro-2{40 -piperazine derivatives and process for the production thereof

ABSTRACT

Compounds of the formula:   AND THE SALTS THEREOF ARE DISCLOSED. In the above formula R1 and R2 are each hydrogen, lower alkoxy, or taken together forming methylenedioxy. These compounds are useful as analgesics, antihistamines, and spasmolytic agents.

United States Patent m Kato et al.

[451 Sept. 2, 1975 [5 1 ,2-DIHYDROINDENE-2-SPlRO-2 PIPERAZINE DERIVATIVES AND PROCESS FOR THE PRODUCTION THEREOF [75] Inventors: Hideo Kato; Eiichi Koshinaka. both of Fukui. Japan [30] Foreign Application Priority Data Nov. 20. 1972 Japan 47415582 [52] U.S. Cl. 260/268 PC; 260/268 TR; 424/232;

424/250 [51 Int. Cl." C07D 295/08 [58] Field of Search 260/268 TR, 268 PC [56] References Cited UNITED STATES PATENTS 2,575,122 1 1/195] Pollard ct al. 260/268 PH Primary Exunzim'r--Riehard J. Gallagher A.\'.s'islunl I:'.\'amincr.|ose Tovar Alan-"qr. Agmu. or F irm-Burgess. Ryan and Wayne [57] ABSTRACT Compounds of the formula:

and the salts thereof are disclosed. In the above formula R and R are each hydrogen. lower alkoxy. or taken together forming methylenedioxy. These compounds are useful as analgesics. antihistamines, and spasmolytic agents.

11- Claims, No Drawings l,2-DIHYDROINDENE-Z-SPIRO-Z'-PIPERAZINE DERIVATIVES AND PROCESS FOR THE PRODUCTION THEREOF The present invention relates to novel piperazine dcrivatives having therapeutic activity and to a process of producing such derivatives.- More particularly. the present invention is directed to novel, 12- dihydroindene-2-spiro-2 -piperazine derivatives repre: sented by the formula:

wherein R and R each representsa hydrogen atom, a lower alkoxy group, preferably up to six carbon atoms, or when combined together, R and R represent a methylenedioxy group, and salts thereof.

According to the present invention, compound(I) can be produced by the reduction of a S-methyl-l-oxol,2,3,4,l l, l la-hexahydro-6H-pyrazino[ l .2- b]isoquinolinium halide derivative represented by the formula:

wherein X is a halogen atom, and R and R; are defined above, with lithium aluminum hydride.

We have found that after studying a various reductive ring open reactions of compound(ll), the spiro compound (I) can be specifically formed by the reduction of compound(ll) using lithium aluminum hydride.

The present invention is carried out by reducing compound (II) with lithium aluminum hydride in organic solvents. The amount of lithium aluminum hydride to be employed is preferably of from 0.01-10 mols, more preferably 5-6 mols, per 1 mol of compound (II).

The reaction can proceed upon cooling or with heating, but preferred reaction temperatures are near the boiling points of the solvents employed. As organic solvents, there can be used absolute ether, absolute tetrahydrofuran, absolute dioxane, etc.

The starting compounds(Il) can easily be obtained by the reaction of l,2,3,4.l 1,1 la-hexahydro-6H pyrazino[ l .2-b]isoquinoline- 1 -one derivatives and methyl halides in a conventional manner. which is hereafter described with reference to synthesis examples.

r The produ ct( l i;n.a ccordance. with the present invention. can be converted 'into,the cor respondingsalts using inorganic acids or. organic acids. Specificexamples of these acids include. hydrochloric acid, hydro-, bromic acid..sulfuric acid. lactic acid. maleic acid. fu maric acid, succininc acid, tartaric acid, salicylic acid, oxalic acid citric acid. et'c.

Compound (I) .produced in accordance with the present invention has analgetic. anti-histamic andspjasmolytic activities. Compound(l) of the present invention itsclf is suitable foruse as a therapeutic agent and isalso useful as an intermediate for preparing other pharmaceutical agents.

. SYNTHESIS EXAMPLE .1

Production of S-methyll-oxo-l ,2,3.4,l 1,1 la hexahydro-6H pyrazino[1.2-b]isoquinolinium iodide I In ml of methanol there was dissolved, with heating. 8.08 g of l,2.3,4,l l,l 1a-hexahydro-6H- pyrazino[ l.2-b.]isoquinoline-l-one. To the solution 17 g of methyl iodide was added dropwise-After the completion of the addition, the reaction was conducted at 60C for 4 hours. After completing the reaction the precipitated crystalswere separated by filtration. Upon recrystallization from water, the desired compound was obtained in an amount of 10.2 g, a? melting point;.of which was 235237C (decomposed). Elemental Analysis: C I-I ONJ Calcd: C. 45.36; .H, 4.98; N, 8.14. Found: C,45.87; H; 5.08; N, 8.1 1.:v

Similar procedureswere repeated to obtain the following compounds.

i. S-Methyl-SS-dimethbxy- 1 OXO-l ,2, 3 ,4,1 1,1 1 a- Y hexaliydro-6I-I-p'yrazino[ 1.2-b]isoquin6linium"- iodide; melting 5mm 2l02l 2C(from methanoly ii. 5-Methyl-8,9 methylenedioxy l -oxo- 1,2,3.4.1 l,1 1a'hexahydro-6I-Ipyrazino[ 1.2

b]isoquinolinium iodide; melting point 280C (from methanol) I I The present invention is further explained in detail with reference to'the following examples. EXAMPLE 1 Synthesisof l methyl-l ,2-dihydroindene-2-spiro-2 '-pip erazine In absolute tetrahydrofuran 3.8 g of lithium aluminum hydride was suspended. To the suspension 3.44 g of S-methyll -oxo-l ,2,3,4,1 1,1 la-hexahydro-6H- pyrazino[ l .2-b]isoquinolinium iodide was added in limited amounts. After the completion of the addition, stirring was continued for 17 hours under reflux. After completing the reaction. water was poured into the reaction mixture to decompose excess lithium aluminum hydride and then filtered. The solids were washed with tetrahydrofuran. The washed liquid was combined with the filtrate. The solvent was removed from the combined liquid by distillation. The residue was dissolved in 10% hydrochloric acid and then washed with ether. The aqueous layer was rendered alkalline with K CO and then extracted with ether. The ethereal layer was washed with water and dehydrated. The residue after removing the ether was subjected to column chromatography using silica gel(Wakogel C-200, tradename made by Wako Junyaku Co., Ltd., developing solvent: chloroform-methanol), to purify.

After removing the solvent by distillation, the residue was converted into the hydrochloride thereof in a conventional manner. Upon recrystallization from a methanol/isopropyl ether mixture. 1.75 g of the hydrochloride of the desired product was obtained. The melting point thereof was 235-240C.

Elemental Analysis: C,;,H,,.,N- ,.2HCl Calcd.: C. 56.73;

H, 7.33; N. 10.18. Found: C. 50.50; H. 7.24; N. 9.79.

The following compounds were obtained in a similar manner.

i. ,(a-Dimethoxy-l '-methyl- 1 .2-dihydroindene-2- spiro-2'-pipera7.ine dihydrochloride; melting point 277280C (from methanol/isopropyl ether) ii. 5 .o-Methylenedioxy-l -methyl- 1 .Z-dihydroindene- 2-spiro2-piperazine dihydrochloride; melting point 275278C (from methanol) What is claimed is:

l. A member selected from the group consisting of a l,Z-dihydroindene-Z-spiro-2'-piperazine of the formula:

NH 1 2 EH3 wherein R, and R each represent a member selected from the group consisting of hydrogen, lower alkoxy of l to 6 carbon atoms. and R, and R when combined together. forma methylenedioxy group, and the corresponding pharmaceutically acceptable acid addition salts thereof.

. 2. A 1.2-dihydroindene-2-spiro-2'piperazine compound of claim 1 wherein R, and R each represent a lower alkoxy group of l to 6 atoms.

3. A l,2-dihydroindene-2-spiro-2'-piperazine pharmaceutically acceptable salt according to claim 1 selected from the group consisting of the hydrochloride,

hydrobromide and sulfate.

4.. A l,2-dihydroindene-2-spiro-2'-piperazine pharmaceutically acceptable salt according to claim 1 selected from the group consisting of the lactate, maleate. fumarate. succinate, tartrate. salicylate, oxalate and citrate.

5. l'-Methyll ,Z-dihydroindene-2-spiro-2'- piperazine, and the corresponding pharmaceutically acceptable acid addition salts thereof.

6. 5.6-Dimethoxy-l inethyl-l .Z-dihydroindene-Z- spiro-2'-pipera7.ine and the corresponding pharmaceu' tically acceptable acid addition salts thereof.

7. 5,6-MethylenedioXy-l -methyl-l ,Z-dihydroindene- 2- spiro-2'-piperazine the corresponding pharmaceutically acceptable acid addition salts thereof.

8. A process of producing a l,2-dihydroindene-2- spiro-2'-piperazine of the formula:

wherein R, and'R each represent a hydrogen atom or a lower alkoxy group of l to 6 carbon atoms, or R, and R when combined together, represent a methylenedioxy group, which consists essentially of reducing with lithium aluminum hydride a S-methyl-l-oxol,2,3,4,l l,l la-hexahydro-6H-pyrazino isoquinolinium halide of the formula:

solute tetrahydrofuran and absolute dioxane. 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A 1.2DIHYDROINDENE-2-SPIRO-2''PIPERAZINE OF THE FORMULA:
 2. A 1,2-dihydroindene-2-spiro-2''-piperazine compound of claim 1 wherein R1 and R2 each represent a lower alkoxy group of 1 to 6 atoms.
 3. A 1,2-dihydroindene-2-spiro-2''-piperazine pharmaceutically acceptable salt according to claim 1 selected from the group consisting Of the hydrochloride, hydrobromide and sulfate.
 4. A 1,2-dihydroindene-2-spiro-2''-piperazine pharmaceutically acceptable salt according to claim 1 selected from the group consisting of the lactate, maleate, fumarate, succinate, tartrate, salicylate, oxalate and citrate.
 5. 1''-Methyl-1,2-dihydroindene-2-spiro-2''-piperazine, and the corresponding pharmaceutically acceptable acid addition salts thereof.
 6. 5,6-Dimethoxy-1''-methyl-1,2-dihydroindene-2-spiro-2''-piperazine and the corresponding pharmaceutically acceptable acid addition salts thereof.
 7. 5,6-Methylenedioxy-1''-methyl-1,2-dihydroindene-2-spiro-2''-piperazine the corresponding pharmaceutically acceptable acid addition salts thereof.
 8. A process of producing a 1,2-dihydroindene-2-spiro-2''-piperazine of the formula:
 9. A process of claim 8 wherein said lithium aluminum-hydride is employed in an amount of 0.01-10 mols per 1 mol of said 5-methyl-1-oxo-1,2,3,4,11,11a-hexahydro-6H-pirazino(1.2-b) isoquinolinium halide derivative.
 10. A process of claim 8 wherein said reduction is conducted at temperatures near the boiling point of the solvent employed.
 11. A process of claim 10 wherein said solvent is selected from the group consisting of absolute ether, absolute tetrahydrofuran and absolute dioxane. 